Zhao, L. et al. Role of p21-activated kinase pathway defects in the cognitive deficits of Alzheimer disease. Nat. Neurosci. 9, 234-242

Faculty of Pharmacy, Laval University, Quebec City, Quebec, Canada
Nature Neuroscience (Impact Factor: 16.1). 03/2006; 9(2):234-42. DOI: 10.1038/nn1630
Source: PubMed


Defects in dendritic spines are common to several forms of cognitive deficits, including mental retardation and Alzheimer disease. Because mutation of p21-activated kinase (PAK) can lead to mental retardation and because PAK-cofilin signaling is critical in dendritic spine morphogenesis and actin dynamics, we hypothesized that the PAK pathway is involved in synaptic and cognitive deficits in Alzheimer disease. Here, we show that PAK and its activity are markedly reduced in Alzheimer disease and that this is accompanied by reduced and redistributed phosphoPAK, prominent cofilin pathology and downstream loss of the spine actin-regulatory protein drebrin, which cofilin removes from actin. We found that beta-amyloid (Abeta) was directly involved in PAK signaling deficits and drebrin loss in Abeta oligomer-treated hippocampal neurons and in the Appswe transgenic mouse model bearing a double mutation leading to higher Abeta production. In addition, pharmacological PAK inhibition in adult mice was sufficient to cause similar cofilin pathology, drebrin loss and memory impairment, consistent with a potential causal role of PAK defects in cognitive deficits in Alzheimer disease.

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    • "In a previous study of a similar set of AD and control cases, significant reductions in some synaptic proteins in AD hippocampus and ITC compared to control brain were observed [19] [20] and there is a well-documented loss of synapses in AD [25] [26] that would predict a correspondingly reduction in neuronal cofilin. Conversely, it has been postulated that greater levels of synaptic cofilin in AD contributes to the mechanism of dendritic pruning and synaptic loss, acting in conjunction with reduced levels of drebrin [2] [27], however our results do not support this as we did not observe increases in cofilin in preparations from AD compared with control brains. We note here that total protein levels do not necessarily reflect the percent of active cofilin which may still be affected. "
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    ABSTRACT: Background: Imaging of human brain as well as cellular and animal models has highlighted a role for the actin cytoskeleton in the development of cell pathology in Alzheimer's disease (AD). Rods and aggregates of the actin-associated protein cofilin are abundant in grey matter of postmortem AD brain and rods are found inside neurites in animal and cell models of AD. Objective: We sought further understanding of the significance of cofilin rods/aggregates to the disease process: Do rods/aggregates correlate with AD progression and the development of hallmark neurofibrillary tangles and neuropil threads? Are cofilin rods/aggregates found in the same neurites as hyperphosphorylated tau? Methods: The specificity of rods/aggregates to AD compared with general aging and their spatial relationship to tau protein was examined in postmortem human hippocampus, inferior temporal cortex, and anterior cingulate cortex. Results: The presence of cofilin rods/aggregates correlated with the extent of tau pathology independent of patient age. Densities of rods/aggregates were fourfold greater in AD compared with aged-matched control brains and rods/aggregates were significantly larger in AD brain. We did not find evidence for our hypothesis that intracellular cofilin rods are localized to tau-positive neuropil threads. Instead, data suggest the involvement of microglia in the clearance of cofilin rods/aggregates and/or in their synthesis in and around amyloid plaques and surrounding neuropil. Conclusion: Cofilin rods and aggregates signify events initiated early in the pathological cascade. Further definition of the mechanisms leading to their formation in the human brain will provide insights into the cellular causes of AD.
    Full-text · Article · Jul 2014 · Journal of Alzheimer's disease: JAD
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    • "Drebrin, which is an actin stabilizing protein important for spine morphogenesis, has been observed to be significantly reduced in AD brain (70e95%) [22]. It has been shown that there is a reciprocal relationship between cofilin and drebrin levels in AD patient samples and in vitro experiments on cultured neurons suggest that cofilin competes for drebrin binding sites on actin filaments [20]. The same study also showed that overexpression of active PAK could rescue Ab induced loss of drebrin . "
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    ABSTRACT: The recent progress in stem cell techniques has broadened the horizon for in vitro disease modeling. For desired in vivo like phenotypes, not only correct cell type specification will be critical, the microenvironmental context will be essential to achieve relevant responses. We demonstrate how a three dimensional (3D) culture of stem cell derived neurons can induce in vivo like responses related to Alzheimer's disease, not recapitulated with conventional 2D cultures. To acquire a neural population of cells we differentiated neurons from neuroepithelial stem cells, derived from induced pluripotent stem cells. p21-activated kinase mediated sensing of Aβ oligomers was only possible in the 3D environment. Further, the 3D phenotype showed clear effects on F-actin associated proteins, connected to the disease processes. We propose that the 3D in vitro model has higher resemblance to the AD pathology than conventional 2D cultures and could be used in further studies of the disease.
    Full-text · Article · Nov 2013 · Biomaterials
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    • "Another key molecule to regulate actin dynamics in dendritic spines is the protein kinase PAK, which is a downstream effector of Rac1. Both in animal models recapitulating AD and brain samples derived from postmortem patients, PAK activation is markedly reduced (Zhao et al. 2006). Moreover, PAK1 and PAK3 promote the formation and growth of dendritic spines by regulating the phosphorylation of the myosin II regulatory light chain kinase and stimulating myosin II (Zhang et al. 2005). "
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    ABSTRACT: Dendritic spines are small protrusions emerging from their parent dendrites, and their morphological changes are involved in synaptic plasticity. These tiny structures are composed of thousands of different proteins belonging to several sub-families such as membrane receptors, scaffold proteins, signal transduction proteins and cytoskeletal proteins. Actin filaments in dendritic spines consist of double helix of actin protomers decorated with drebrin and ADF/cofilin, and the balance of the two is closely related to the actin dynamics, which may govern morphological and functional synaptic plasticity. During development, the accumulation of drebrin-binding type actin filaments is one of the initial events occurring at the nascent excitatory postsynaptic site, and play a pivotal role in spine formation as well as small GTPases. It has been recently reported that microtubules transiently appear in dendritic spines in correlation with synaptic activity. Interestingly, it is suggested that microtubule dynamics might couple with actin dynamics. In this review we will summarize the contribution of both actin filaments and microtubules to the formation and regulation of dendritic spines, and further discuss the role of cytoskeletal deregulation in neurological disorders. This article is protected by copyright. All rights reserved.
    Full-text · Article · May 2013 · Journal of Neurochemistry
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